Process for synthesis of syn azido epoxide and its use as intermediate for the synthesis of amprenavir &amp; saquinavir

ABSTRACT

Disclosed herein is a novel route of synthesis of syn azide epoxide of formula 5, which is used as a common intermediate for asymmetric synthesis of HIV protease inhibitors such as Amprenavir, Fosamprenavir, Saquinavir and formal synthesis of Darunavir and Palinavir obtained by Cobalt-catalyzed hydrolytic kinetic resolution of racemic anti-(2SR,3SR)-3-azido-4-phenyl-1,2-epoxybutane (azido-epoxide).

TECHNICAL FIELD

The invention relates to a novel process for the synthesis of syn-azido epoxide, intermediate. Further, the invention relates to short and efficient asymmetric synthesis of HIV protease inhibitors such as amprenavir, fosamprenavir, saquinavir and formal synthesis of darunavir and palinavir via syn azido epoxide with high enantiomeric excess as a common intermediate obtained by Cobalt-catalyzed hydrolytic kinetic resolution of racemic anti-(2SR,3SR)-3-azido-4-phenyl-1,2-epoxybutane (azido-epoxide).

BACKGROUND AND PRIOR ART

The etiologic agent such as human immunodeficiency virus type 1 and type 2(HIV-1 and 2), that causes acquired immunodeficiency syndrome (AIDS), encodes for a specific aspartyl proteinase (HIV-protease). The inhibition of HIV-proteases by peptidomimetic structures incorporating a hydroxyethylamine (HEA) isostere offers a promising approach for the treatment of AIDS.

Many potent drugs such as amprenavir, fosamprenavir saquinavir and, darunavir, palinavir which belong to the HEA class, have complex structures equipped with multiple stereogenic centers. Due to the potential biological importance of these HIV inhibitors, considerable effort has been directed at methods for their synthesis.

The HIV protease inhibitors has been developed as one of the most promising chemotherapeutic agents for the treatment of acquired immune deficiency syndrome (AIDS) and it exhibits the complex structure equipped with multiple steriogenic centers. Thus, synthetic organic chemist has been attracted towards development of an efficient and practical synthetic route for these inhibitors. amprenavir 1 developed by Vertex and GlaxoSmithKline, is an HIV protease inhibitor that was approved by the FDA in 1999. fosamprenavir 2, launched in 2003, is a prodrug with increased therapeutic efficacy.

There are couple of publications disclosed the synthesis of HIV protease inhibitors, some of relevant prior arts mentioned herein below;

WO/2000/018384 publication discloses a pharmaceutical combination comprising (S)2 ethyl 7 fluoro 3oxo 3,4dihydro 2H quinoxaline1carboxylic acid isopropyl ester or a physiologically functional derivative thereof and 4 amino N((2syn,3S)2hydroxy4phenyl3((S) tetrahydrofuran 3 yloxycarbonylamino)butyl)Nisobutylbenzenesulfonamide (amprenavir) or a physiologically functional derivative thereof.

U.S. Pat. No. 6,436,989 discloses fosamprenavir calcium and other salts of fosamprenavir such as sodium, potassium and magnesium, their pharmaceutical compositions and methods of treating HIV infection and inhibiting aspartyl protease activity in a mammal. U.S. Pat. No. 6,514,953 discloses polymorphic Form I of fosamprenavir calcium, its pharmaceutical composition, and its method of use for treatment of an HIV infection, wherein the process for the preparation of a fosamprenavir or its salts comprising i) reacting a compound of formula (II) with a phosphorylating agent; and further reduction.

Further preparation of saquinavir is described in U.S. Pat. No. 5,196,438 and also described in European Patent No. EP432695, wherein (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid was hydrogenated with hydrogen gas at higher pressure in presence of Rhodium on carbon as catalyst using 90% acetic acid and final step involves treatment of (2S)-N-[(1S,2R)-3-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-octahydro-1H-isoquinolin-2-yl]-1-benzyl-2-hydroxy-propyl]-2-amino-butanediamide with quinaldic acid in presence of hydroxybenzotriazole and dicyclohexylcarbodiimide using N-ethylmorpholine as base

Also the preparation of darunavir is reported in International publication No. WO9967417 and WO9967254.

The multistep stereoselective synthesis of palinavir, a potent HIV protease inhibitor is disclosed in J. Org. Chem., 1997, 62 (11), pp 3440-3448 by Pierre L. Beaulieu et al.

Although several methods have been tried for the syntheses of HIV protease inhibitors, some of them require chiral auxiliaries or use of chiral building blocks and exotic reagents, involvement of longer reaction sequence, expensive catalysts coupled with low enantiomeric excess, making the process non feasible industrially

Additionally, several synthetic approaches of azido epoxide (5) the key chiral building block in the synthesis of HEA-based HIV protease inhibitors have been reported in the literature.

An article titled “Efficient Synthesis of 2(S)-[1(S)-Azido-2-phenylethyl]oxirane” by Sangwoo Park, Sangmi Lee, and Ho-Jung Kang in Bull. Korean Chem. Soc. 2008, Vol. 29, No. 5 1073, discloses efficient synthesis of 2(S)-[1(S)-azido-2-phenylethyl]oxirane (1) from acetonide 2 as a starting material by 9 steps with two purification steps at alcohol 3 and oxirane 1 respectively in overall yield of 48%. providing an expedient route to the facile, practical and large production of the desired epoxide 1 and other related structural motives from the cheaper D-isoascorbic acid.

WO 99/67254 provides a retroviral protease-inhibiting compound represented by formula (I), or a pharmaceutically acceptable salt, a prodrug, or an ester thereof, wherein A is a group of formula (II), (III), (IV), or (V);

The said patent application further provides a method of synthesizing the multidrug-resistant, retroviral protease-inhibiting compounds such as for example, ritonavir, saquinavir, indinavir, amprenavir, AZT, ddl, ddC, d4T, 3TC, ABV (abacavir), DLV (delaviridine), and PFA (foscarnet). of the present invention.

The said synthesis method is generally illustrated in FIG. 4, wherein a compound of Formula (I) is synthesized in several steps starting from azidoepoxide (i), wherein amine (ii) is nucleophilically added to azidoepoxide (i), providing aminoalcohol (iii) which is then reacted with intermediate (iv), which can be, displaced by the amine of aminoalcohol (iii), to provide azide (v); reduction of azide (v), provides intermediate (vi), which is subsequently coupled with activated bicyclic ligand (vii) gives compound (I) (cf below scheme).

However the few methods that relate to the synthesis of the azido epoxide compound suffer from limitations such as the use of chiral building blocks, introduction of chirality in the early stages, long reaction sequences, the use of expensive catalysts, low % ee, and so on, and hence, are not amenable for scale-up studies.

Therefore there is a need in the art to provide an efficient method of synthesizing azido epoxide compound (5) which can be further used to provide an efficient synthetic method for the preparation of HIV protease inhibitors such as amprenavir, fosamprenavir, saquinavir, darunavir, palinavir and their structural analogues that proceed with high enantiosectivites (99% ee) in a concise manner.

Accordingly the present invention provide a new synthetic route for the preparation of racemic azido epoxide (5) from commercially available allylic alcohol.

Accordingly, the present inventors have further developed new synthetic route for the preparation of HIV protease inhibitors, comprising hydrolytic kinetic resolution (HKR) of racemic azido epoxide as a key step to obtain HIV protease inhibitors in high yield and high enantioselectivity. Further the process developed by the inventor is efficient, cost effective as it involves simple organic reagents and water and industrially viable as well as socially important.

OBJECT OF INVENTION

In view of above, the objective of the invention is to provide a short, enantioselective synthesis of HIV protease inhibitors such as amprenavir, saquinavir, fosamprenavir and formal synthesis of darunavir, palinavir with high enantioselectivities (99% ee) via Co-catalyzed hydrolytic kinetic resolution (HKR) of racemic anti-(2SR,3SR)-3-azido-4-phenyl-1,2-epoxybutane i.e. racemic azido-epoxide as chiral inducing key reactions, wherein the route of synthesis of racemic anti-(2SR,3SR)-3-azido-4-phenyl-1,2-epoxybutane i.e. racemic azido-epoxide is also through a novel route.

SUMMARY

Accordingly the present in provides an enantioselective synthesis of syn azido epoxide of formula (+)-5 comprising:

-   -   wherein, ‘A’ is substituted or unsubstituted aryl group, wherein         substituents are selected from (C1-C8) alkyl, aryl, arylalkyl,         halo, (C1-C8) alkoxy,     -   i) subjecting allylic alcohol to epoxidation with         m-chlorobenzoic acid (mCPBA) to obtain racemic epoxy alcohol;     -   ii) ring opening of epoxide with azide anion in presence of         Lewis acid to produce the corresponding anti-azido alcohol,         followed by selective tosylation of primary alcohol to afford         tosylate;     -   iii) treating tosylate with base to obtain racemic azido         epoxide; and     -   iv) subjecting racemic azido epoxide to hydrolytic kinetic         resolution to obtain corresponding 1,2-diol and syn azido         epoxide followed by isolating syn azido epoxide with         enantiomeric purity >98%.     -   In an embodiment of the invention, wherein the allylic alcohol         is aryl substituted or unsubstituted butene alcohol.

In another embodiment of the invention, wherein the Lewis acid is selected from the group consisting of BF3, anhyd. AlCl3, PF5, TiCl4, Ti(OiPr)4, zinc bromide and cerium(III) Chloride.

In still another embodiment of the invention, wherein the source of azide anion is selected from inorganic azide such as sodium azide, chlorine, bromine, and iodine azides or organic azide such as tosyl azide, trimethylsilyl azide in suitable organic solvent.

In a further embodiment of the invention, wherein the hydrolytic kinetic resolution is carried out in presence of (S,S)-Co(Salen)acetate complex in molar concentration in the range of 0.2-0.8 mol % in suitable organic solvent.

Accordingly the present invention also provides an enantioselective synthesis of HIV protease inhibitors from syn azido epoxide of formula (+)-5 comprising converting said syn azido epoxide to said HIV protease inhibitors, wherein said syn azido epoxide is prepared by a process comprising:

-   -   i) subjecting allylic alcohol to epoxidation with         m-chlorobenzoic acid (mCPBA) to obtain racemic epoxy alcohol;     -   ii) ring opening of epoxide with azide anion in presence of         Lewis acid to produce the anti-azido alcohol, followed by         selective tosylation of primary alcohol to afford tosylate;     -   iii) treating tosylate with base to obtain racemic azido         epoxide;     -   iv) subjecting racemic azido epoxide to hydrolytic kinetic         resolution to obtain corresponding 1,2-diol and syn azido         epoxide followed by isolating syn azido epoxide with         enantiomeric purity of >98%.

In an embodiment of the invention, wherein the HIV protease inhibitors are selected from amprenavir, fosamprenavir, saquinavir, darunavir, palinavir.

In another embodiment of the invention, wherein the allylic alcohol is aryl substituted or unsubstituted

In yet another embodiment of the invention, wherein the Lewis acid is selected from the group consisting of BF3, anhyd. AlCl3, PF5, TiCl₄, Ti(OiPr)₄, zinc bromide and cerium(III) Chloride.

In still another embodiment of the invention, wherein the source of azide anion is selected from inorganic azide such as sodium azide, chlorine, bromine, and iodine azides or organic azide such as tosyl azide, trimethylsilyl azide in suitable organic solvent.

In a further embodiment of the invention, wherein the hydrolytic kinetic resolution is carried out in presence of (S,S)-Co(Salen)acetate complex in molar concentration in the range of 0.2-0.8 mol. % in suitable organic solvent.

In a further embodiment of the invention, wherein the conversion of syn azido epoxide into amprenavir comprising steps of (i) subjecting syn azido epoxide to a regiospecific ring opening with iso butyl amine to give azido alcohol ii) converting azido alcohol into its nosylate to obtain azido nosylate iii) converting azido nosylate into amprenavir by using standard sequence of reactions such as azide reduction; condensation with (S)-3-hydroxytetrahydrofuran and reduction of the nitro group to an amine functionality.

In one of the embodiment of the invention, wherein the nosylating agent may be selected from, para-nitro-benzenesulfonylisocyanate, para nitrobenzenesulfonyl anhydride or para nitrobenzene sulfonyl chloride.

Still another embodiment of the invention, wherein reducing agent may be selected from SnCl₂, LiAlH₄ or any suitable salt of Li, Al, Mg, Al, Fe, Cu, Ag, Na in solvent.

In a further embodiment of the invention, wherein base may be selected from inorganic base such as alkali or alkaline metal oxide, hydroxides, carbonates, bicrabonates, hydride, particularly K₂CO₃, NaOH, Na2CO₃, NaHCO₃, CaOH, KOH, C_(S)CO₃, wherein the organic base is selected from alkyl amine, arylamine, heterocylic amine such as branched or linear alkyl like n-butyl, triethyl, trimethyl, or sec-propyl amines, aniline, pyridine, pyrollidine, amino acid either alone or mixtures thereof in suitable-solvent.

In a further embodiment of the invention, wherein the suitable organic solvent may be selected from the group consisting of polar aprotic such as DCM, THF, Ethyl acetate, acetone, DMF, acetonitrile, DMSO or polar protic solvents such as lower alcohol particularly (C1-C6) alkyl alcohol, water, acetic acid or non-polar solvents such as hexane, benzene, toluene, chloroform, pet. ether, 1,4-dioxane, heptane either alone or mixtures thereof.

In a further embodiment of the invention, wherein syn azido epoxide is converted to saquinavir by treating the same with [(3S)-(3α,4αβ,8αβ)]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide in presence of silica gel (230-400, 6 Å mesh) in organic solvent to yield 2-(3(S)-Azido-2(R)-hydroxy-4-phenylbutyl)-N-tert-butyldecahydro-(4aS,8aS) isoquinoline-3(S)-carbaxomide, which is converted into sequinavir by the known methods.

ABBREVIATIONS

Co-catalyzed HKR: Cobalt catalyzed hydrolytic kinetic resolution

DESCRIPTION OF THE INVENTION

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

In the preferred embodiment, the present invention provides an efficient route for the synthesis of the HIV protease inhibitors selected from the group consisting of amprenavir (1), fosamprenavir (2), saquinavir (3), darunavir (4), palinavir (6) based on hydrolytic kinetic resolution (HKR) of racemic azido epoxide, as common key intermediate which is also known as racemic azido oxirane.

In one embodiment, the invention provides asymmetric synthesis for preparation key intermediate i.e., two stereocentered azido epoxide (+)-5 from commercially available allylic alcohol as depicted in scheme 1.

The syn azido epoxide (+)-5 is chemically known as 2(S)-[1′(S)-azido-2-phenylethyl]oxirane. The enantioselective synthesis of two stereocentered azido epoxide (+)-5 comprises steps of

i) subjecting allylic alcohol (7) to epoxidation with m-chlorobenzoic acid (mCPBA) to obtain racemic epoxy alcohol (8);

ii) ring opening of epoxide (8) with azide anion in presence of Lewis acid to produce the anti-azido alcohol (9), followed by selective tosylation of primary alcohol to afford tosylate (10);

iii) treating tosylate with base to obtain racemic azido epoxide (11);

iv) subjecting racemic azido epoxide (11) to hydrolytic kinetic resolution to obtain the corresponding 1,2-diol (12) and azido epoxide (+)-5, subsequent separation gives (+)-5 in high enantiomeric purity.

wherein, ‘A’ is substituted or unsubstituted aryl group, wherein substituents are selected from (C1-C8) alkyl, aryl, arylalkyl, halo, (C1-C8) alkoxy.

According in scheme 1, allylic alcohol 7 is prepared in quantitative yield by known techniques, particularly from phenylacetaldehyde in two steps: (i) a Wittig-Horner reaction in presence of benzaldehyde, and ethyl triphenylphosphoranylidene acetate in suitable solvent at (90° C.) and (ii) a selective ester reduction in presence of LiAlH4, catalytic AlCl3, dry ether, 0° C.). The allylic alcohol is particularly selected from (E)-4-phenyl but-2-en-1-ol, wherein phenyl group is either substituted or unsubstituted.

The alcohol (7) is then subjected to epoxidation with m-chlorobenzoic acid (mCPBA) to obtain racemic epoxy alcohol (8) in more than 85% yield. The Lewis acid-catalyzed ring opening of epoxide (8) with azide anion produces the anti-azido alcohol (9) (more than 95% yield) in a highly regioselective manner (regioisomer distribution: 27:1). In the ring opening step the Lewis acid is selected from the group consisting of BF3, anhyd. AlCl3, PF5, TiCl₄, Ti(OiPr)₄, zinc bromide, cerium(III) Chloride and other metal salts, wherein source of azide anion can be obtained from inorganic azide such as sodium azide, chlorine, bromine, and iodine azides or organic azide such as tosyl azide, trimethylsilyl azide and the like thereof in suitable organic solvent. The temperature is maintained above 50° C. to reduce the reaction time, preferably temperature is in the range of 60° C.-80° C.

Further the desired regioisomer (9) is separated by column chromatography and transformed into racemic azido epoxide (11) comprising selective tosylation of the primary alcohol followed by base treatment to obtain epoxide (11) with yield more than 90%. The racemic azido epoxide (11) is subsequently subjected to HKR with the (S,S)-salen Co(OAc) complex (0.2-0.8 mol %) in suitable organic solvent and H₂O (0.3 to 0.6 equiv), which affords the corresponding diol (2R,3R)-3-azido-4-phenylbutane-1,2-diol (12) and syn azido-epoxide i.e. 2(S)-[1′(S)-azido-2-phenylethyl]oxirane (5) with high yield and enantiomeric purity, particularly more than 98% ee. The desired intermediated compound azido epoxide (+)-5 is separated from diol (−)-12 by simple column chromatography technique.

The regioselective toslylation is carried out in presence of Dibutyltin oxide (DBTO) wherein tosylating agent is selected from tosyl chloride, tosyl anhydride, p-toluenesulfonyl acid, with addition of a dichloromethane solution of catalytic amount of 4-dimethylaminopyridine (DMAP) and base.

The base is selected from inorganic base such as alkali or alkaline metal oxide, hydroxides, carbonates, bicrabonates, hydride and like thereof particularly K₂CO₃, NaOH, Na2CO₃, NaHCO₃, CaOH, KOH, C_(S)CO₃ either alone or combination thereof, however the organic base is not limited to alkyl amine, arylamine, heterocylic amine such as branched or linear alkyl like n-butyl, triethyl, trimethyl, or sec-propyl amines, aniline, pyridine, pyrollidine, amino acid and mixtures thereof in lower alcohol such as ethanol, methanol, propanol or, butanol The tosylation is preferably carried out at low temperature.

Additionally, the HKR uses water as the only reagent, no added solvent, and low loading of recyclable chiral cobalt-based salen complexes to afford the terminal epoxides and 1,2-diol in high yield and high enantiomeric excess and no effluent is generated. Also the instant method is easy to perform at higher scales (kgs).

In another embodiment, the enantioenriched syn-azido epoxide thus obtained is subjected to regioselective azide displacement of epoxy alcohol and insertion of heterocyclic moiety as shown in schemes 2 to 5 to obtain desired HIV protease inhibitors such as amprenavir 1, fosamprenavir 2, saquinavir 3, darunavir 4 and palinavir 6 in high yield and enantiomeric purity >98% in a concise manner.

In an embodiment, the present invention provides asymmetric synthesis of amprenavir (1), from key intermediate syn-azido epoxide (+)-5 which is represented by scheme 2,

In accordance with scheme 2, compound 5 is subjected to a regiospecific ring opening with isobutylamine in suitable solvent to give azidoalcohol 13, which is subsequently protected as its nosylate 14 in presence of base and organic solvent at lower temperature. The nosylating agent is selected from, 4-nitro-benzenesulfonylisocyanate, para nitrobenzene sulfonyl anhydride or para nitrobenzene sulfonylschloride.

Azido nosylate 14 was finally transformed into amprenavir 1 in three steps with an overall yield more than 90% by following a standard sequence of reactions: (i) azide reduction in presence of triphenylphosphine and suitable organic solvent; (ii) condensation with N-hydroxysuccinimidyl carbonate of (S)-3-hydroxytetrahydrofuran (A″) at ambient condition in presence of strong base; and (iii) reduction of the nitro group to an amine functionality in presence of reducing agent like SnCl₂, LiAlH₄ or any suitable salt of Li, Al, Mg, Al, Fe, Cu, Ag, Na in solvent at high temperature (50-80° C.).

In another embodiment, the invention provides synthesis of fosamprenavir which is phosphonooxy salt of amprenavir and can be prepared by treatment of phosphoric acid on the amprenavir synthesized by instant process (cf scheme 3 herein below). However treatment of phosphoric acid can be performed by the known technique used in the preparation of protease inhibitors.

In another embodiment, the invention provides synthesis of saquinavir (3) from the key intermediate azido-epoxide comprises treatment of azido epoxide (+)-5 with [(3S)-((3α,4αβ,8αβ)]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide in presence of silica gel (230-400, 6 Å mesh) in organic solvent to give more than 85% yield of key azido alcohol (16) in highly regioselective fashion. The transformation of 16 into saquinavir 3 is known in the literature. The synthesis of saquinavir is represented herein below in scheme 4.

In yet another embodiment, the formal synthesis of darunavir starting with syn azido-epoxide (+)-5, which is prepared by hydrolytic kinetic resolution (HKR) of racemic azido epoxide according to the invention.

In yet another embodiment, the invention discloses formal synthesis of palinavir starting with syn azido-epoxide (+)-5, which is prepared by hydrolytic kinetic resolution (HKR) of racemic azido epoxide according to the invention.

The organic solvent mentioned according to the invention is selected from the group consisting of organic solvents, wherein the organic solvents are polar aprotic such as DCM, THF, Ethyl acetate, acetone, DMF, acetonitrile, DMSO; polar protic solvents such as lower alcohol particularly (C1-C6) alkyl alcohol, water, acetic acid; non-polar solvents such as hexane, benzene, toluene, chloroform, pet. ether, 1,4-dioxane, heptane either alone or mixtures thereof. Additionally the purification or separation of crude product can be accomplished by known techniques viz. extraction, column chromatography in a suitable organic solvent with the aid of instruments such as TLC, HPLC, GC, mass spectroscopy, or distillation, crystallization, derivatization.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of examples and for purpose of illustrative discussion of preferred embodiments of the invention only and are not limiting the scope of the invention.

EXAMPLES Materials and Methods

The Solvents were purified and dried by standard procedures prior to use. Optical rotations were measured using sodium D line on a JASCO-181 digital polarimeter. IR spectra were recorded on a Thermo Scientific-Nicolet 380 FT-IR and absorption is expressed in cm⁻¹. ¹H NMR and ¹³C NMR spectra were recorded on Brucker AC-200 spectrometer unless mentioned otherwise. Elemental analysis was carried out on a Carlo Erba CHNS-O analyzer. Purification was carried out using column chromatography (60-120 mesh). Enantiomeric excesses were determined on Agilent HPLC instrument equipped with a suitable chiral column.

Example 1 Synthesis of (E)-Ethyl 4-phenylbut-2-enoate

To a stirred solution of phenyl acetaldehyde (7.0 g, 58.3 mmol) in benzene (150 mL) was added (ethoxycarbonylmethylene)triphenylphosphorane (22.3 g, 64.1 mmol) and the resulting mixture heated under reflux for 6 h. After the reaction was complete, solvent was removed under reduced pressure to provide the crude product, which was then purified by column chromatography over silica gel using petroleum ether/EtOAc (19:1) to give α,β unsaturated ester 6 (10.6 g, 96%) as a colorless oil. IR: (CHCl₃, cm⁻¹): υ_(max) 699, 1041, 1098, 1158, 1270, 1301, 1669, 1721, 1782, 2858, 2984; ¹H NMR (200 MHz, CDC₃): δ 1.28 (t, J=7.1 Hz, 3H), 3.23 (d, J=6.8 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 6.21-6.35 (m, 11-1), 6.48 (d, J=15.6 Hz, 1H), 7.14-7.37 (m, 5H); ¹³C NMR (50 MHz, CDC₃): δ 14.2, 38.4, 60.1, 122.4, 126.7, 128.6, 128.7, 137.6, 147.1, 166.2; Anal. Calcd for C₁₂H₁₄O₂: C, 75.76; H, 7.42. Found: C, 75.65; H, 7.41%.

Example 2 Synthesis of (E)-4-Phenylbut-2-en-1-ol (7)

To a stirred suspension of LiAlH₄ (2.4 g, 63.1 mmol) in dry Et₂O (60 mL) at 0° C. under nitrogen atmosphere was added dropwise a solution of anhydrous AlCl₃ (1.7 g, 12.6 mmol) in dry Et₂O (30 mL). The reaction mixture was stirred at the same temperature for 30 min. To this stirred suspension, ester obtained in example 1 (8.0 g, 42.1 mmol) in dry Et₂O (30 mL) was added dropwise over a period of 15 min and the resulting mixture stirred at 0° C. for 1 h. Then it was quenched with ice-water and filtered through celite and the residue was washed with ethyl acetate (3×30 mL). The combined organic layer was dried over anhyd. Na₂SO₄, concentrated and the crude product was purified by column chromatography using petroleum ether/EtOAc (4:1) to afford the pure allylic alcohol 7 (5.4 g, 87%) as a colorless oil. IR: (CHCl₃, cm⁻¹): υ_(max) 694, 744, 966, 1049, 1107, 1364, 1454, 2857, 2932, 3385; ¹H NMR (200 MHz, CDC₃): δ 1.22 (br s, 1H), 3.38 (d, J=6.4 Hz, 2H), 4.12 (t, J=4.8 Hz, 21-1), 5.62-5.93 (m, 2H), 7.15-7.32 (m, 5H); ¹³C NMR (50 MHz, CDC₃): δ 36.4, 61.9, 126.0, 126.3, 127.2, 128.5, 132.7, 137.2; Anal. Calcd for C₁₀H₁₂O: C, 81.04; H, 8.16. Found: C, 81.02; H, 8.15%.

Example 3 Synthesis of (3-Benzyloxiran-2-yl) methanol (8)

To a solution of allylic alcohol 7 (5.0 g, 33.7 mmol) in dry CH₂Cl₂ (60 mL) at 0° C. was added m-chloroperbenzoic acid (8.7 g, 50.6 mmol) in small portions. The resulting solution was stirred for 8 h until complete consumption of starting materials (the progress of the reaction was monitored by TLC). The reaction mixture was quenched with water and the aqueous layer was extracted with CH₂Cl₂ (3×30 mL). The organic layer was washed with aq. 10% solution of NaHCO₃ (15 mL). The combined organic layer was dried over anhyd. Na₂SO₄ and the solvent was removed under reduced pressure. The crude product was purified by column chromatography over silica gel using petroleum ether/EtOAc (4:1) to give the corresponding epoxide 8 (4.8 g, 88%) as a viscous gum. IR: (CHCl₃, cm⁻¹): υ_(max) 700, 991, 1028, 1055, 1106, 1452, 2921, 3404; ¹H NMR (200 MHz, CDC₃): δ 2.88-2.99 (m, 3H), 3.17-3.23 (m, 1H), 3.57-3.72 (m, 1H), 3.85-3.95 (m, 1H), 7.18-7.34 (m, 5H); ¹³C NMR (50 MHz, CDC₃): δ 34.2, 67.1, 78.9, 87.5, 125.5, 127.5, 128.4, 140.8; Anal. Calcd for C₁₀H₁₂O₂: C, 73.15; H, 7.37. Found: C, 73.25; H, 7.47%.

Example 4 Synthesis of 3-Azido-4-phenylbutane-1,2-diol (9)

A mixture of freshly distilled Ti(O^(i)Pr)₄ (9.5 mL, 32.1 mmol) and TMSN₃ (8.4 mL, 64.1 mmol) was refluxed in dry benzene (20 mL) under nitrogen for 5 h until the solution became clear. To this was added a solution of the epoxy alcohol 8 (3.5 g, 21.3 mmol) in 40 mL dry benzene. The resulting mixture was heated under reflux for 15 min, cooled to room temperature and the solvent was removed in vacuo. The concentrate was diluted with 20 mL of diethyl ether and treated with 15 mL of aq. 5% H₂SO₄. The aqueous layer was extracted with CH₂Cl₂ and the combined organic layers were dried over anhyd. Na₂SO₄ and concentrated to afford the crude product which was purified by column chromatography using petroleum ether:EtOAc (3:2) to give azido diol 9 (4.2 g, 96%) as a colorless solid. mp 80-81° C. (lit.¹⁰ mp 80.5-82° C.); IR: (CHCl₃, cm⁻¹): υ_(max) 696, 753, 1039, 1106, 1242, 1554, 2105, 2923, 2960, 3280; ¹H NMR (200 MHz, CDCl₃): δ 1.79 (t, J=5.3 Hz, 1H), 2.47 (d, J=5.2 Hz, 1H), 2.80 (dd, J=14.2, 8.6 Hz, 1H), 3.02 (dd, J=14.1, 4.2 Hz, 1H), 3.59-3.81 (m, 4H), 7.24-7.32 (m, 5H); ¹³C NMR (50 MHz, CDCl₃): δ 37.0, 63.2, 65.6, 73.2, 126.9, 128.7, 129.3, 137.2; Anal. Calcd for C₁₀H₁₃N₃O₂: C, 57.96; H, 6.32; N, 20.28. Found: C, 57.85; H, 6.28; N, 20.22%.

Example 5 Synthesis of 2-(1-Azido-2-phenylethyl) oxirane (11)

A mixture containing dry Et₃N (4.0 mL, 28.9 mmol), Bu₂SnO (72 mg, 2 mol %), and N,N-Dimethyl-4-aminopyridine (177 mg, 10mol %) was added to a solution of azido diol 9 (3 g, 14.5 mmol) in dry CH₂Cl₂ (40 mL) at 0° C. Solid p-toluene sulfonyl chloride (2.9 g, 15.9 mmol) was then added to the reaction mixture. The resulting mixture was allowed to stir at room temperature for 3 h. It was then diluted with water (10 mL) and extracted with dichloromethane (3×20 mL). The organic phase was washed with brine solution, dried over anhyd. Na₂SO₄ and concentrated in vacuo to give the crude product 10 (5.0 g), which was used in the next step without purification. To a solution of tosylate 10 (3.0 g, 8.3 mmol) in methanol (25 mL) was added K₂CO₃ (2.3 g, 16.6 mmol) at 0° C. and the resulting mixture was stirred at 25° C. for 1 h. After the completion reaction (monitored by TLC), solvent was evaporated and the residue was extracted with diethyl ether (3×20 mL). The combined ether layer was dried over anhyd. Na₂SO₄ and concentrated to give the crude product, which was then purified by column chromatography over silica gel using petroleum ether/EtOAc (19:1) to give the azido epoxide 11 (1.5 g) as a colorless liquid (90% over two steps). IR: (CHCl₃, cm⁻¹): υ_(max) 701, 760, 930, 1082, 1216, 1455, 1496, 2109, 2401, 2927, 3020; ¹H NMR (200 MHz, CDC₃): δ 2.79-2.86 (m, 3H), 2.94 (dd, J=13.9, 4.6 Hz, 1H), 3.01-3.07 (m, 1H), 3.51-3.61 (m, 1H), 7.22-7.37 (m, 5H); ¹³C NMR (50 MHz, CDC₃): δ 38.2, 45.0, 52.9, 63.6, 126.9, 128.5, 129.3, 136.5; Anal. Calcd for C₁₀H₁₁N₃O: C, 63.48; H, 5.86; N, 22.21. found: C, 63.58; H, 5.55; N, 22.19%.

Example 6 Synthesis of 2(S)-[1′(S)-azido-2-phenylethyl]oxirane (5)

To a solution of (S,S)-Co-complex (43 mg, 0.1 mmol) in toluene (4.0 mL) was added acetic acid (40 mg, 7.3 mmol). It was allowed to stir at 0° C. in open air for 30 min over which time the color of the solution changed from orange-red to a dark brown. It was then concentrated in vaccuo to obtain the Co-salen complex as brown-colored solid. To a solution of Co-salen complex (16 mg, 0.5 mol %) and azido epoxide 11 (1.0 g, 5.3 mmol) in THF (0.5 mL) at 0° C. was added H₂O (46 mg, 2.6 mmol) dropwise over 5 min. The reaction mixture was allowed to warm to 25° C. and stirred for 14 h. After completion of reaction (monitored by TLC), solvent was removed in vacuo. The crude product was purified by column chromatography over silica gel. Solvent system: petroleum ether: EtOAc (19:1) for chiral azido epoxides 5 (480 mg, 48%) and petroleum ether: EtOAc (3:2) for chiral azido diol 12 (537 mg, 49%). [α]²⁰ _(D): +13.1 (c=1, CHCl₃) {lit.⁷ [α]²⁰ _(D): +12.9 (c=1.15, CHCl₃)}; 99% ee by chiral HPLC analysis (Chiralcel OD-H column, n-hexane/iPrOH, 97:03, 0.5 mL/min) retention time 17.517 (99.60%) and 15.747 (0.40%) for azido epoxide 5.

Example 7 (2R,3R)-3-Azido-4-phenylbutane-1,2-diol (12)

Optical rotation: [α]²⁰ _(D): −30.8 (c=1, CHCl₃); 98% ee by chiral HPLC analysis (Chiralcel OD-H column, n-hexane/iPrOH, 90:10, 0.5 mL/min) retention time 13.512 (99.02%) and 11020 (0.98%).

Example 8 Synthesis of Nosylate (14)

To a solution of azido epoxide 5 (0.2 g, 1.1 mmol) in dry isopropanol (2.0 mL), isobutylamine (0.5 mL, 5.3 mmol) was added and the reaction mixture was stirred for 5 h at 50° C. It was concentrated under reduced pressure and dried in vaccuo to give 263 mg of amino alcohol 13, which was used for the next step without purification. To a stirred solution of 13 (0.1 g, 0.4 mmol) in, of dry CH₂Cl₂ (2.0 mL) was added triethylamine (64 μL, 0.5 mmol) and 4-nitrobenzenesulfonyl chloride (0.11 g, 0.5 mmol) at 0° C. The resulting mixture was stirred for 30 min at this temperature and warmed to room temperature. It was stirred for 12 h and poured into saturated aq. NaHCO₃ solution (3 mL) and extracted with Et₂O (3×5 mL). The organic layer was dried over anhyd. Na₂SO₄ and concentrated to give the crude product. Column chromatographic purification using petroleum ether:EtOAc (4:1) provided nosylate 14 (160 mg) as a pure colorless solid (89% over two steps). mp 115-117° C.; [α]²⁰ _(D): −5.3 (c=1, CHCl₃); IR: (CHCl₃, cm⁻¹): υ_(max) 607, 745, 1089, 1160, 1312, 1350, 1531, 2110, 2957, 3499; ¹H NMR (200 MHz, CDC₃): δ 0.86-0.93 (m, 6H), 1.74-1.91 (m, 1H), 2.76-2.96 (m, 2H), 3.01-3.14 (m, 3H), 3.20-3.23 (m, 1H), 3.57-3.79 (m, 2H), 7.24-7.36 (m, 5H), 7.98 (d, J=8.9 Hz, 2H), 8.38 (d, J=8.9 Hz, 2H); ¹³C NMR (50 MHz, CDC₃): δ 19.7, 20, 26.9, 36.9, 52.2, 58.1, 66.49, 71.4, 124.4, 127.0, 128.5, 128.7, 129.3, 136.8, 144.5, 150.1; Anal. Calcd for C₂₀H₂₅N₅O₅S: C, 53.68; H, 5.63; N, 15.65; S, 7.17. Found: C, 53.58; H, 5.54; N, 15.45; S, 7.12%.

Example 9 Synthesis of N-Hydroxyl succinimidyl carbonate of (S)-3-hydroxytetrahydrofuran

To a magnetically stirred solution of (S)-3-hydroxytetrahydrofuran (0.2 g, 2.3 mmol) in 7 mL of dry acetonitrile was added dry triethylamine (0.9 mL, 6.8 mmol) followed by N,N disuccinimidyl carbonate (0.9 g, 3.4 mmol) at room temperature. The mixture was stirred for 4 h and poured into EtOAc (15 mL). The ethyl acetate layer was washed with saturated aq. NaHCO₃ solution (5 mL) and dried over anhyd. Na₂SO₄. The organic extract was concentrated under reduced pressure to give the crude product. Silica gel column chromatographic purification provided the carbonate compound (0.4 g, 82%).

Example 10 Synthesis of 4-Nitro-N-((2R(syn),3S)-2-hydroxy-4-phenyl-3((S)-tetrahydrofuran-3-yloxy carbonylamino)-butyl)-N-isobutylbenzenesulfonamide (15)

To a stirred solution of nosylate 14 (0.1 g, 0.2 mmol) in 2 mL of dry THF, triphenyl phosphine (0.06 g, 0.2 mmol) was added as a lump at 25° C. and the reaction mixture was stirred for 30 min. To this H₂O (0.004 g, 0.2 mmol) was added and the stirring continued for 29 h. After completion of reaction, solvent was removed in vacuo, water was added and extracted with ethyl acetate (3×5 mL). The organic layer was washed with brine, dried over anhyd. Na₂SO₄, concentrated to give the crude amine (0.09 g) as a yellow solid which was used in the following step without purification. To a solution of the above crude amine (0.08 g, 0.2 mmol) in 1 mL of dry CH₂Cl₂ was added N-hydroxyl succinimidyl carbonate of (S)-3-hydroxytetrahydrofuran (0.04 g, 0.2 mmol) (see previous experiment for its preparation) and dry triethylamine (32 μL, 0.2 mmol) at room temperature. The reaction mixture was stirred for 2 h and concentrated to remove solvent. The residue was dissolved in ethyl acetate and washed with 5% saturated aq. NaHCO₃ followed by 5% aq. solution of citric acid. The combined organic layers were washed with brine and dried over anhyd. Na₂SO₄. The mixture was concentrated to give the crude product, which was purified by column chromatography using petroleum ether: EtOAc (7:3) to give carbamate derivative 15 (0.09 g) as a colorless solid (89% over two steps). mp 161-163° C.; [a]²⁰ _(D): +15.5 (c=0.2, CHCl₃); IR: (CHCl₃, cm⁻¹): υ_(max) 606, 745, 1029, 1088, 1109, 1159, 1312, 1350, 1530, 1605, 1709, 2960, 3388; ¹H NMR (200 MHz, CDC₃): δ 0.87 (d, J=6.9 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H), 1.83-1.94 (m, 2H), 2.09-2.13 (m, 1H), 2.93-2.96 (m, 4H), 3.13-3.16 (m, 2H), 3.59-3.65 (m, 2H), 3.75-3.83 (m, 5H), 4.88 (br s, 1H), 5.13 (br s, 1H), 7.22-7.32 (m, 5H), 7.95 (d, J=8.8 Hz, 2H), 8.4 (d, J=8.8 Hz, 2H); ¹³C NMR (50 MHz, CDC₃): δ 19.6, 19.8, 26.8, 32.5, 35.1, 52.6, 55.1, 57.5, 66.5, 71.9, 72.7, 75.4, 124.0, 126.6, 128.2, 128.4, 129.1, 136.94, 144.5, 149.8, 155.9; Anal. Calcd for C₂₅H₃₃N₃O₈S: C, 56.06; 11, 6.21; N, 7.85; S, 5.99. Found: C, 56.16; H, 6.18; N, 7.65; S, 5.93%.

Example 11 Synthesis of Amprenavir (1)

To a solution of carbamate nitro derivative 15 (0.05 g, 0.09 mmol) in 2 mL of EtOAc was added SnCl₂.2H₂O (0.1 g, 0.5 mmol) at 70° C. The reaction mixture was heated for 1 h until starting material disappeared and the solution cooled to room temperature. It was then poured into saturated aq. NaHCO₃ solution and extracted with EtOAc. The organic extract was dried over anhyd. Na₂SO₄ and concentrated under reduced pressure. It was purified over chromatography using petroleum ether:EtOAc (3:2) to give amprenavir 1 (0.04 g, 90%). IR: (CHCl₃, cm⁻¹): υ_(max) 757, 1090, 1149, 1316, 1504, 1597, 1633, 1705, 2960, 3371; ¹H NMR (200 MHz, CDC₃): δ 0.86 (d, J=5.7 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H), 1.78-2.21 (m, 3H), 235-3.11 (m, 6H), 3.58-4.11 (m, 7H), 4.25 (s, 2H), 5.01 (br s, 1H), 5.07 (br s, 1H), 6.65 (d, J=8.4 Hz, 2H), 7.20-7.28 (m, 5H), 7.51 (d, J=8.4 Hz, 2H); ¹³C NMR (50 MHz, CDC₃): δ 19.9, 20.2, 27.3, 32.8, 35.4, 35.7, 53.8, 55.0, 58.6, 66.8, 72.6, 73.2, 75.3, 114.0, 125.9, 126.5, 1280.4, 129.5, 137.7, 150.9, 155.9; Anal. Calcd for C₂₅H₃₅N₃O₆S: C, 59.39; H, 6.98; N, 8.31; S, 6.34. Found: C, 59.36; H, 6.81; N, 8.25; S, 6.29%.

Example 12 Preparation of 2-(3(S)-Azido-2(R)-hydroxy-4-phenylbutyl)-N-tert-butyldecahydro-(4aS,8aS) isoquinoline-3(S)-carbaxomide (16)

Silica gel (Merck grade 60, 230-400 mesh, 6 Å; 0.2 g), was added to a solution of [3S-(3α,4αβ,8αβ)]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide (0.06 g, 0.3 mmol) and epoxide 5 (0.05 g, 0.3 mmol) in CHCl₃ (1 mL) and the resulting suspension was concentrated under reduced pressure. After standing at room temperature for 16 h, the light brown solid obtained was loaded to a column packed with silica gel and eluted with petroleum ether:EtOAc (7:3) to give the azido alcohol 16 (0.09 g, 85%), essentially a single distereomer, as a colorless solid. mp 154.2° C. (lit.¹² mp 153-5° C.); [α]²⁰ _(D): −75.5 (c=1 CHCl₃) {lit.⁷ [α]²⁰ _(D): −75.7 (c=1, CHCl₃)}; IR: (CHCl₃, cm⁻¹): υ_(max) 1045, 1153, 1226, 1385, 1454, 1519, 1652, 2101, 2861, 2924, 3439; ¹H NMR (200 MHz, CDC₃): δ 1.33 (s, 9H), 1.25-2.05 (m, 12H), 2.43 (m, 2H), 2.68-3.09 (m, 5H), 3.56-3.64 (m, 3H), 5.84 (s, 1H), 7.23-7.32 (m, 5H); ¹³C NMR (50 MHz, CDC₃): δ 20.8, 25.9, 26.1, 28.7, 30.6, 31, 33.3, 36.1, 36.7, 51.1, 58.4, 60.8, 66.9, 70.3, 126.7, 128.6, 129.4, 137.7, 173.3; ESI-MS: m/z 450.5 [M+Na]⁺ Anal. Calcd for C₂₄H₃₇N₅O₂: C, 67.42; H, 8.72; N, 16.38. Found: C, 67.40; H, 8.83; N, 16.35%. 

1. An enantioselective synthesis of syn azido epoxide of formula (+)-5 comprising:

wherein, ‘A’ is substituted or unsubstituted aryl group, wherein substituents are selected from (C1-C8) alkyl, aryl, arylalkyl, halo, (C1-C8) alkoxy, i) subjecting allylic alcohol to epoxidation with m-chloroperbenzoic acid (mCPBA) to obtain racemic epoxy alcohol; ii) ring opening of epoxide with azide anion in presence of Lewis acid to produce the corresponding anti-azido alcohol, followed by selective tosylation of primary alcohol to afford tosylate; iii) treating tosylate with base to obtain racemic azido epoxide; and iv) subjecting racemic azido epoxide to hydrolytic kinetic resolution to obtain corresponding 1,2-diol and syn azido epoxide followed by isolating syn azido epoxide with enantiomeric purity >98%.
 2. The process according to claim 1, wherein the allylic alcohol is aryl substituted or unsubstituted butene alcohol.
 3. The process according to claim 1, wherein the Lewis acid is selected from the group consisting of BF3, anhyd. A1C13, PF5, TiC14, Ti(OiPr)4, zinc bromide and cerium(III) Chloride.
 4. The process according to claim 1, wherein the source of azide anion is selected from inorganic azide such as sodium azide, chlorine, bromine, and iodine azides or organic azide such as tosyl azide, trimethylsilyl azide in suitable organic solvent.
 5. The process according to claim 1, wherein the hydrolytic kinetic resolution is carried out in presence of (S,S)-Co(Salen)acetate complex in molar concentration in the range of 0.2-0.8 mol % in suitable organic solvent.
 6. An enantioselective synthesis of HIV protease inhibitors from syn azido epoxide of formula (+)-5 comprising converting said syn azido epoxide to said HIV protease inhibitors, wherein said syn azido epoxide is prepared by a process comprising: i) subjecting allylic alcohol to epoxidation with m-chloroperbenzoic acid (mCPBA) to obtain racemic epoxy alcohol; ii) ring opening of epoxide with azide anion in presence of Lewis acid to produce the anti-azido alcohol, followed by selective tosylation of primary alcohol to afford tosylate; iii) treating tosylate with base to obtain racemic azido epoxide; iv) subjecting racemic azido epoxide to hydrolytic kinetic resolution to obtain corresponding 1,2-diol and syn azido epoxide followed by isolating syn azido epoxide with enantiomeric purity of >98%.
 7. The process according to claim 6, wherein the HIV protease inhibitors are selected from amprenavir, fosamprenavir, saquinavir, darunavir, palinavir.
 8. The process according to claim 6, wherein the allylic alcohol is aryl substituted or unsubstituted butene alcohol.
 9. The process according to claim 6, wherein the Lewis acid is selected from the group consisting of BF3, anhyd. A1C13, PF5, TiCl4, Ti(OiPr)₄, zinc bromide and cerium(III) Chloride.
 10. The process according to claim 6, wherein the source of azide anion is selected from inorganic azide such as sodium azide, chlorine, bromine, and iodine azides or organic azide such as tosyl azide, trimethylsilyl azide in suitable organic solvent.
 11. The process according to claim 6, wherein the hydrolytic kinetic resolution is carried out in presence of (S,S)-Co(Salen)acetate complex in molar concentration in the range of 0.2-0.8 mol % in suitable organic solvent.
 12. The process according to claim 6, wherein the conversion of syn azido epoxide into amprenavir comprising steps of (i) subjecting syn azido epoxide to a regiospecific ring opening with iso butyl amine to give azido alcohol ii) converting azido alcohol into its nosylate to obtain azido nosylate iii) converting azido nosylate into amprenavir by using standard sequence of reactions such as azide reduction; condensation with (S)-3-hydroxytetrahydrofuran and reduction of the nitro group to an amine functionality.
 13. The process according to claim 12, wherein the nosylating agent is selected from, para-nitro-benzenesulfonylisocyanate, para nitrobenzenesulfonyl anhydride or para nitrobenzene sulfonyl chloride.
 14. The process according to claim 12, wherein reducing agent is selected from SnCl₂, LiAlH₄ or any suitable salt of Li, Al, Mg, Al, Fe, Cu, Ag, Na in solvent.
 15. The process according to claim 6, wherein base is selected from inorganic base such as alkali or alkaline metal oxide, hydroxides, carbonates, bicrabonates, hydride, particularly K₂C0₃NaOH, Na2CO₃, NaHCO₃, CaOH, KOH, C_(s)C0₃, wherein the organic base is selected from alkyl amine, arylamine, heterocylic amine such as branched or linear alkyl like n-butyl, triethyl, trimethyl, or sec-propyl amines, aniline, pyridine, pyrollidine, amino acid either alone or mixtures thereof in suitable solvent.
 16. The process according to claim 4, claims, wherein the suitable organic solvent is selected from the group consisting of polar aprotic such as DCM, THF, Ethyl acetate, acetone, DMF, acetonitrile, DMSO or polar protic solvents such as lower alcohol particularly (Cl-C6) alkyl alcohol, water, acetic acid or non-polar solvents such as hexane, benzene, toluene, chloroform, pet. ether, 1,4-dioxane, heptane either alone or mixtures thereof.
 17. The process according to claim 6, wherein syn azido epoxide is converted to saquinavir by treating. the same with [(3S)-(3α,4αβ,8αβ)]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide in presence of silica gel (230-400, 6 mesh) in organic solvent to yield 2-(3(S)-Azido-2(R)-hydroxy-4-phenylbutyl)-N-tert-butyldecahydro-(4aS,8aS) isoquinoline-3(S)-carbaxomide, which is converted into sequinavir by the known methods.
 18. The process according to claim 5, wherein the suitable organic solvent is selected from the group consisting of polar aprotic such as DCM, THF, Ethyl acetate, acetone, DMF, acetonitrile, DMSO or polar protic solvents such as lower alcohol particularly (Cl-C6) alkyl alcohol, water, acetic acid or non-polar solvents such as hexane, benzene, toluene, chloroform, pet. ether, 1,4-dioxane, heptane either alone or mixtures thereof.
 19. The process according to claim 10, wherein the suitable organic solvent is selected from the group consisting of polar aprotic such as DCM, THF, Ethyl acetate, acetone, DMF, acetonitrile, DMSO or polar protic solvents such as lower alcohol particularly (Cl-C6) alkyl alcohol, water, acetic acid or non-polar solvents such as hexane, benzene, toluene, chloroform, pet. ether, 1,4-dioxane, heptane either alone or mixtures thereof.
 20. The process according to claim 11, wherein the suitable organic solvent is selected from the group consisting of polar aprotic such as DCM, THF, Ethyl acetate, acetone, DMF, acetonitrile, DMSO or polar protic solvents such as lower alcohol particularly (Cl-C6) alkyl alcohol, water, acetic acid or non-polar solvents such as hexane, benzene, toluene, chloroform, pet. ether, 1,4-dioxane, heptane either alone or mixtures thereof. 